Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function

Abstract

The venom of the spider Phoneutria nigriventer contains several toxins that have bioactivity in mammals and insects. Accidents involving humans are characterized by various symptoms including penile erection. Here we investigated the action of Tx2-6, a toxin purified from the P. nigriventer spider venom that causes priapism in rats and mice. Erectile function was evaluated through changes in intracavernosal pressure/mean arterial pressure ratio (ICP/MAP) during electrical stimulation of the major pelvic ganglion (MPG) of normotensive and deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Nitric oxide (NO) release was detected in cavernosum slices with fluorescent dye (DAF-FM) and confocal microscopy. The effect of Tx2-6 was also characterized after intracavernosal injection of a non-selective nitric oxide synthase (NOS) inhibitor, L-NAME. Subcutaneous or intravenous injection of Tx2-6 potentiated the elevation of ICP/MAP induced by ganglionic stimulation. L-NAME inhibited penile erection and treatment with Tx2-6 was unable to reverse this inhibition. Tx2-6 treatment induced a significant increase of NO release in cavernosum tissue. Attenuated erectile function of DOCA-salt hypertensive rats was fully restored after toxin injection. Tx2-6 enhanced erectile function in normotensive and DOCA-salt hypertensive rats, via the NO pathway. Our studies suggest that Tx2-6 could be important for development of new pharmacological agents for treatment of erectile dysfunction.

Exploring the global animal biodiversity in the search for new drugs – Spiders, scorpions, horseshoe crabs, sea spiders, centipedes, and millipedes

“…Further exploration of these compounds may lead to the development of valuable medicines for treating, among others, erectogenic conditions [76][77][78], botulism [97,98], malignant neoplasms [114,116,222,223], autoimmune disorders [133], microbial [161,165,210,215,245] and parasitic infections [147], and chronic pain [207], as well as improved bacterial endotoxin detection [159] and innovative sunscreens [178]. These advances are much needed when considering the high global incidence of erectogenic conditions [250], autoimmune disorders [251], and cancer [252], the worldwide threat of bioterrorism [99], and the increasing resistance of microbial [253] and parasitic infections [254] to exisiting medications.…”

“…So far, two such substances have been identified, namely the peptides PnTx2-5 and PnTx2-6 (Pn from P. nigriventer which are also referred to as Tx2-6 and Tx2-5, respectively [76][77][78]. These compounds delayed the fast inactivation of voltage-dependent sodium channels [79] resulting in a persistent sodium current that caused depolarization block, and stimulated the activity of nitric oxide synthase and the release of nitric oxide, enhancing cGMP levels and promoting vasodilation and increasing blood flow [76,80,81].…”

“…PnTx2-5 and PnTx2-6 acted on cavernosal tissue preparation in vitro [76,77], in laboratory mice [82], as well as in animal models of hypertension [77,83], type-1 diabetes mellitus [80], and ageing [81]. Importantly, these compounds seemed to preferentially aim at testicles and penis [76] but at a site different from that targeted by sildenafil (Viagra ® ) [81].…”

Some arachnidan peptides with potential medical application

“…These venoms, as well as some peptides purified from them, have shown efficiency in promoting priapism and erection in different experimental models (53,115,116,(119)(120)(121).…”

“…These venoms have been described as potentially useful for future discovery and development of new biologically active molecules with medical application (66,115,116,122). The crude venom of Phoneutria nigriventer contains potent neurotoxins that cause excitatory symptoms (53,56).…”